Control of immune cell infiltration into tumors by endothelial Notch signaling

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Cancer is a genetic disease and most research is still focused on alterations in cancer cells. However, cancer cells grow in close interaction with their microenvironment. The stromal response to tumor cells (e.g. immune cell infiltration, angiogenesis and generation of extracellular matrix) is part of the host defense program, but unfortunately several aspects of this stromal reprogramming support tumor progression and metastasis. Furthermore, there is increasing evidence that the microenvironment substantially contributes to resistance against chemotherapy in metastatic disease. This emphasizes the urgent need for better understanding the bi-directional interactions between cancer cells and surrounding stromal cells to ultimately develop better therapies. In this project we will address the crosstalk between endothelial cells with immune and cancer cells during cancer progression. This project was inspired by our observation of increased Notch signaling activity in tumor blood vessels of human tumor samples. Our previous data show that Notch ligands are frequently expressed on tumor cells but also on tumor-infiltrating neutrophils, which can activate Notch1 receptors on endothelial cells. We have established a large repertoire of methods, animal models and unpublished data showing that sustained endothelial Notch signaling facilitates the transmigration of tumor cells through blood vessel walls and the infiltration of myeloid cells into tumors. Thereby, endothelial Notch signaling changes the transcriptome, which leads to a pro-inflammatory, senescent-like phenotype. This includes secretion of chemokines like CCL2 and adhesion factors like VCAM1. These proteins facilitate tumor cell transmigration and myeloid cell infiltration into tumors. Furthermore, endothelial Notch signaling promoted the homing of circulating tumor cells. As such our preliminary data showed that sustained endothelial Notch signaling promotes metastasis.We aim at deciphering the mechanisms how manipulation of Notch signaling activity in endothelial cells influences infiltration of immune cells and tumor progression. Therefore we will make use of cell culture systems and mouse models for inducible endothelial cell-specific Notch gain and loss of function. Most of these studies will be performed in a model of advanced stage ovarian carcinoma. This model allows the distinction of Notch-mediated effects on immune cell infiltration and tumor angiogenesis. The ultimate goal will be to decipher if endothelial Notch inhibition is a novel therapeutic tool to limit tumor progression and metastatic spreading.